Validation of the BOADICEA model for epithelial tubo-ovarian cancer risk prediction in UK Biobank.

BACKGROUND: The clinical validity of the multifactorial BOADICEA model for epithelial tubo-ovarian cancer (EOC) risk prediction has not been assessed in a large sample size or over a longer term. METHODS: We evaluated the model discrimination and calibration in the UK Biobank cohort comprising 199,429 women (733 incident EOCs) of European ancestry without previous cancer history. We predicted 10-year EOC risk incorporating data on questionnaire-based risk factors (QRFs), family history, a 36-SNP polygenic risk score and pathogenic variants (PV) in six EOC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 and PALB2). RESULTS: Discriminative ability was maximised under the multifactorial model that included all risk factors (AUC = 0.68, 95% CI: 0.66-0.70). This model was well calibrated in deciles of predicted risk with calibration slope=0.99 (95% CI: 0.98-1.01). Discriminative ability was similar in women younger or older than 60 years. The AUC was higher when analyses were restricted to PV carriers (0.76, 95% CI: 0.69-0.82). Using relative risk (RR) thresholds, the full model classified 97.7%, 1.7%, 0.4% and 0.2% women in the RR < 2.0, 2.0 ≤ RR < 2.9, 2.9 ≤ RR < 6.0 and RR ≥ 6.0 categories, respectively, identifying 9.1 of incident EOC among those with RR ≥ 2.0. DISCUSSION: BOADICEA, implemented in CanRisk ( www.canrisk.org ), provides valid 10-year EOC risks and can facilitate clinical decision-making in EOC risk management.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.

The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.

Improving the communication of multifactorial cancer risk assessment results for different audiences: a co-design process.

BACKGROUND: Multifactorial cancer risk prediction tools, such as CanRisk, are increasingly being incorporated into routine healthcare. Understanding risk information and communicating risk is challenging and healthcare professionals rely substantially on the outputs of risk prediction tools to communicate results. This work aimed to produce a new CanRisk report so users can directly access key information and communicate risk estimates effectively. METHODS: Over a 13-month period, we led an 8-step co-design process with patients, the public, and healthcare professionals. Steps comprised 1) think aloud testing of the original CanRisk report; 2) structured feedback on the original report; 3) literature review; 4) development of a new report prototype; 5) first round of structured feedback; 6) updating the new report prototype; 7) second round of structured feedback; and 8) finalising and publishing the new CanRisk report. RESULTS: We received 56 sets of feedback from 34 stakeholders. Overall, the original CanRisk report was not suitable for patients and the public. Building on the feedback, the new report has an overview of the information presented: section one summarises key information for individuals; sections two and three present information for healthcare professionals in different settings. New features also include explanatory text, definitions, graphs, keys and tables to support the interpretation of the information. DISCUSSION: This co-design experience shows the value of collaboration for the successful communication of complex health information. As a result, the new CanRisk report has the potential to better support shared decision-making processes about cancer risk management across clinical settings.

Large-scale analysis of whole genome sequencing data from formalin-fixed paraffin-embedded cancer specimens demonstrates preservation of clinical utility.

Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England's 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an "FFPEImpact" score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many.

Economic evaluation of extended panel analysis in cancer patients with historical NHS diagnostic germline genetic testing - A modeling study based on real-world data.

BACKGROUND: The South West Thames Centre for Genomics implemented a wider diagnostic Next Generation Sequencing (NGS) gene panel for eligible cancer patients undergoing diagnostic testing whilst restricting data analysis and reporting for BRCA1/BRCA2/PALB2/CHEK2 1100delC only as per contemporaneous guidelines. This study investigated the cost-utility of reanalyzing existing diagnostic grade extended panel data for truncating germline pathogenic variants (GPVs) in known moderate risk cancer susceptibility genes (CSGs) and performing follow-up genetic testing for first-degree relatives if patients have an identified CSG allele. METHODS: Reanalysis of existing NGS data was undertaken in 889 samples from cancer patients contemporaneously eligible through the NHS England National Genomic Test Directory (NGTD) codes R207 (ovarian) or R208 (breast) who had tested negative for BRCA1/BRCA2/PALB2 and CHEK2 1100delC founder variant. We modeled the cost and health outcomes for comparisons between: 1. Extending reanalysis to ATM truncating GPVs (partial extended testing) versus historical genetic testing, and 2. Extending analysis to ATM truncating GPV/BRIP1 truncating GPV/CHEK2 truncating GPV excluding CHEK2 1100delC/RAD51C truncating GPV/RAD51D truncating GPV (full extended testing) versus historical genetic testing. RESULTS: For partial extended testing, the ICER compared with historical genetic testing was UK£49,671/QALY. For full extended testing, the ICER compared with historical genetic testing of historical genetic testing was UK£5716/QALY. The full extended testing remained cost-effective with a 30% increase in genetic testing cost. CONCLUSION: Where existing NGS data for cancer susceptibility genes is stored to diagnostic standard in UK laboratories, this study suggests it is cost-effective to analyze, report and clinically manage patients and relatives by extended analysis to an 8-gene panel compared to the historical genetic testing.

Introduction and impact of routine whole genome sequencing in the diagnosis and management of sarcoma.

BACKGROUND: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing. METHODS: Introduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre. RESULTS: WGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases. CONCLUSION: Introduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients.

Joint ABS-UKCGG-CanGene-CanVar consensus regarding the use of CanRisk in clinical practice.

BACKGROUND: The CanRisk tool, which operationalises the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is used by Clinical Geneticists, Genetic Counsellors, Breast Oncologists, Surgeons and Family History Nurses for breast cancer risk assessments both nationally and internationally. There are currently no guidelines with respect to the day-to-day clinical application of CanRisk and differing inputs to the model can result in different recommendations for practice. METHODS: To address this gap, the UK Cancer Genetics Group in collaboration with the Association of Breast Surgery and the CanGene-CanVar programme held a workshop on 16th of May 2023, with the aim of establishing best practice guidelines. RESULTS: Using a pre-workshop survey followed by structured discussion and in-meeting polling, we achieved consensus for UK best practice in use of CanRisk in making recommendations for breast cancer surveillance, eligibility for genetic testing and the input of available information to undertake an individualised risk assessment. CONCLUSIONS: Whilst consensus recommendations were achieved, the meeting highlighted some of the barriers limiting the use of CanRisk in clinical practice and identified areas that require further work and collaboration with relevant national bodies and policy makers to incorporate wider use of CanRisk into routine breast cancer risk assessments.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology and variant interpretation. This VCEP made specifications for ACMG/AMP guidelines for the ataxia telangiectasia mutated (ATM) gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules for ATM were modified from the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar and reevaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 the 33 pilot variants were not VUS leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.

Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers.

BACKGROUND: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres. METHODS: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information. RESULTS: The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options. CONCLUSION: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).

The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

OBJECTIVES: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

Breast cancer risk assessment for prescription of menopausal hormone therapy in women with a family history of breast cancer: an epidemiological modelling study.

BACKGROUND: Menopausal hormone therapy (MHT) can alleviate menopausal symptoms but has been associated with an increased risk of breast cancer. MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking. AIM: To quantify the risks associated with MHT use in women with varying breast cancer family histories of developing and dying from breast cancer. DESIGN AND SETTING: An epidemiological modelling study for women in England using the BOADICEA breast cancer prediction model and data relating to MHT use and breast cancer risk taken from research by the Collaborative Group on Hormonal Factors in Breast Cancer. METHOD: The risk of developing and dying from breast cancer between the ages of 50 and 80 years was modelled in women with four different breast cancer family history profiles: 'average', 'modest', 'intermediate', and 'strong' by using 1) background risks of breast cancer by age and family history, 2) relative risks for breast cancer associated with MHT use, and 3) 10-year breast cancer-specific net mortality rates. This study modelled use of combined oestrogen-progestogen MHT (cyclical or continuous) and oestrogen-only MHT. RESULTS: For a woman of 'average' family history taking no MHT, the cumulative breast cancer risk (age 50-80 years) is 9.8%, and the risk of dying from the breast cancer is 1.7%. In this model, 5 years' exposure to combined-cyclical MHT (age 50-55 years) was calculated to increase these risks to 11.0% and 1.8%, respectively. For a woman with a 'strong' family history taking no MHT, the cumulative breast cancer risk is 19.6% (age 50-80 years), and the risk of dying from the breast cancer is 3.2%. With 5 years' exposure to MHT (age 50-55 years), this model showed that these risks increase to 22.4% and 3.5%, respectively. CONCLUSION: In this model, both family history and MHT are associated with increased risk of breast cancer. Estimates of the risks of breast cancer associated with MHT for women with different family histories can be used to support decision making around MHT prescription for women experiencing menopausal symptoms.

Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort study.

Background: Second primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets. Methods: The cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan-Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression. Findings: Both genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99-2.06) females; 55.4 (35.5-82.4) males) and non-breast (1.10 (1.09-1.11) females, 1.10 (1.00-1.20) males) SPC risks. Non-breast SPC risks were higher for females younger at BC diagnosis (SIR: 1.34 (1.31-1.38) <50 y, 1.07 (1.06-1.09) ≥50 y) and more socioeconomically deprived (SIR: 1.00 (0.98-1.02) least deprived quintile, 1.34 (1.30-1.37) most). Interpretation: Enhanced SPC surveillance may benefit BC survivors, although specific recommendations require more detailed multifactorial risk and cost-benefit analyses. The associations between deprivation and SPC risks could provide clinical management insights. Funding: CRUK Catalyst Award CanGene-CanVar (C61296/A27223). Cancer Research UK grant: PPRPGM-Nov 20∖100,002. This work was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline.

PURPOSE: To develop recommendations for germline mutation testing for patients with breast cancer. METHODS: An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS: Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS: BRCA1/2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing, regardless of family history. BRCA1/2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history.Additional information is available at www.asco.org/breast-cancer-guidelines.

Long-term outcomes of hysterectomy with bilateral salpingo-oophorectomy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to provide an up-to-date systematic review of "the long-term outcomes of bilateral salpingo-oophorectomy at the time of hysterectomy" and perform a meta-analysis for the reported associations. DATA SOURCES: Our study updated a previous systematic review by searching the literature using PubMed, Web of Science, and Embase for publications between January 2015 and August 2022. STUDY ELIGIBILITY CRITERIA: Our study included studies of women who had a hysterectomy with bilateral salpingo-oophorectomy vs women who had a hysterectomy with ovarian conservation or no surgery. METHODS: The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Adjusted hazard ratios were extracted and combined to obtain fixed effect estimates. RESULTS: Compared with hysterectomy or no surgery, hysterectomy with bilateral salpingo-oophorectomy in young women was associated with decreased risk of breast cancer (hazard ratio, 0.78; 95% confidence interval, 0.73-0.84) but with an increased risk of colorectal cancer (hazard ratio, 1.27; 95% confidence interval, 1.10-1.47). In addition, it was associated with an increased risk of total cardiovascular diseases, coronary heart disease, and stroke with hazard ratios of 1.18 (95% confidence interval, 1.11-1.25), 1.17 (95% confidence interval, 1.10-1.25), and 1.20 (95% confidence interval, 1.10-1.31), respectively. Compared with no surgery, hysterectomy with bilateral salpingo-oophorectomy before the age of 50 years was associated with an increased risk of hyperlipidemia (hazard ratio, 1.44; 95% confidence interval, 1.25-1.65), diabetes mellitus (hazard ratio, 1.16; 95% confidence interval, 1.09-1.24), hypertension (hazard ratio, 1.13; 95% confidence interval, 1.06-1.20), dementia (hazard ratio, 1.70; 95% confidence interval, 1.07-2.69), and depression (hazard ratio, 1.39; 95% confidence interval, 1.22-1.60). The evidence on the association with all-cause mortality in young women showed substantial heterogeneity between the studies (I2=85%; P<.01). CONCLUSION: Hysterectomy with bilateral salpingo-oophorectomy was associated with multiple long-term outcomes. The benefits of the addition of bilateral salpingo-oophorectomy to hysterectomy should be balanced against the risks.

Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

BACKGROUND: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. METHODS: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). RESULTS: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. CONCLUSION: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.

Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome.

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.